The U.S. Veteran population suffers from high rates of depression and significant mental health symptom burden. Sadly, suicide rates reflect this as well, being significantly higher for Veterans relative to the non-Veteran populations. Therefore, a critical need exists to identify the complex gene x environment interactions and the underlying neural substrates that drive the pathogenesis of depression. Clinical observations abound associating reduced brain-derived neurotrophic factor (BDNF) expression with depression and increased BDNF expression with effective antidepressant responses. Rodent models have reliably confirmed those associations, and revealed important mechanistic roles for hippocampal BDNF expression in the response to antidepressant drugs. However, the neurobiological mechanisms by which reduced BDNF expression might engender vulnerability to the development of depression remain unclear. The existence of a high frequency polymorphism of the bdnf gene (Val66Met; allelic frequency 20- 35%) in humans that reduces BDNF protein levels makes this a highly relevant biomedical problem that needs to be addressed. Inflammation or chronic stress, as environmental precipitants of depression represent an ideal context to conduct translationally relevant mechanism based experiments aimed at understanding this gene x environment interaction. Our exciting new preliminary data, in both human and mouse model systems, suggest that BDNF may play an important negative regulatory role on microglial activation state, and disruption of the BDNF system sensitizes mice to the development of inflammation or stress-induced depressive-like behavior. The experiments proposed in this application will utilize two of the quintessential mouse models of environmentally-induced depressive-like behavior and novel methodology in a human postmortem system to better understand the interactions between the BDNF system and microglia activation state in relation to depression scores and prefrontal cortical (PFC)- dependent symptom profiles (e.g. impulsivity, cognitive flexibility and attention). We propose to test the hypothesis that BDNF deficiency induces vulnerability to development of PFC- dependent depressive-like behaviors as a direct result of increased microglial reactivity and neurotoxic tryptophan metabolism. If successful, the new experimental data that emerge from these experiments can be immediately `reverse translated' to the clinic to develop novel diagnostic and therapeutic approaches for vulnerable patients.